Aminoalkyl substituted pyrrolo[3,2-e] pyridine and pyrrolo[2,3-b]pyrimidine derivatives: modulators of CRF1 receptors

ABSTRACT

Disclosed are compounds of the formula:                    
     wherein Ar, Q 1 , Q 2 , R 1 , W and X are substituents as defined herein, which compounds are water-soluble CRF 1  receptor antagonists, and are therefore useful for the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.

This is a division of application Ser. No. 09/283,410, filed Apr. 1,1999, which claims priority from application Serial No. 60/080,434,filed Apr. 2, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to aminoalkyl substitutedpyrrolo[3,2-e]pyridine and pyrrolo[2,3-b]pyrimidine derivatives,pharmaceutical compositions containing such compounds, and their use forthe treatment of psychiatric disorders and neurological diseases,including major depression, anxiety-related disorders, post-traumaticstress disorder, supranuclear palsy and feeding disorders, as well astreatment of immunological, cardiovascular or heart-related diseases andcolonic hypersensitivity associated with psychopathological disturbanceand stress.

2. Description of the Related Art

Corticotropin releasing factor (herein referred to as CRF), a 41 aminoacid peptide, is the primary physiological regulator ofproopiomelanocortin (POMC) derived peptide secretion from the anteriorpituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851(1983); W. Vale et al., Science 213:1394 (1981)]. In addition to itsendocrine role at the pituitary gland, immunohistochemical localizationof CRF has demonstrated that the hormone has a broad extrahypothalamicdistribution in the central nervous system and produces a wide spectrumof autonomic, electrophysiological and behavioral effects consistentwith a neurotransmitter or neuromodulator role in brain [W. Vale et al.,Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39(1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There isalso evidence that CRF plays a significant role in integrating theresponse of the immune system to physiological, psychological, andimmunological stressors [J. E. Blalock, Physiological Reviews 69:1(1989); J. E. Morley, Life Sci. 41:527 (1987)].

Clinical data provide evidence that CRF has a role in psychiatricdisorders and neurological diseases including depression,anxiety-related disorders and feeding disorders. A role for CRF has alsobeen postulated in the etiology and pathophysiology of Alzheimer'sdisease, Parkinson's disease, Huntington's disease, progressivesupranuclear palsy and amyotrophic lateral sclerosis as they relate tothe dysfunction of CRF neurons in the central nervous system [for reviewsee E. B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF issignificantly increased in the cerebral spinal fluid (CSF) of drug-freeindividuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Bankiet al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol.Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989).Furthermore, the density of CRF receptors is significantly decreased inthe frontal cortex of suicide victims, consistent with a hypersecretionof CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. Inaddition, there is a blunted adrenocorticotropin (ACTH) response to CRF(i.v. administered) observed in depressed patients [P. W. Gold et al.,Am J. Psychiatry 141:619 (1984); F. Holsboer et al.,Psychoneuroendocrinology 9:147(1984); P. W. Gold et al., New Eng. J.Med. 314:1129 (1986)]. Preclinical studies in rats and non-humanprimates provide additional support for the hypothesis thathypersecretion of CRF may be involved in the symptoms seen in humandepression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. Thereis preliminary evidence that tricyclic antidepressants can alter CRFlevels and thus modulate the numbers of CRF receptors in brain[Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

There has also been a role postulated for CRF in the etiology ofanxiety-related disorders. CRF produces anxiogenic effects in animalsand interactions between benzodiazepine/non-benzodiazepine anxiolyticsand CRF have been demonstrated in a variety of behavioral anxiety models[D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J.Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using theputative CRF receptor antagonist α-helical ovine CRF (9-41) in a varietyof behavioral paradigms demonstrate that the antagonist produces“anxiolytic-like” effects that are qualitatively similar to thebenzodiazepines [C. W Berridge and A. J. Dunn Horm. Behav. 21:393(1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrineand receptor binding studies have all demonstrated interactions betweenCRF and benzodiazepine anxiolytics providing further evidence for theinvolvement of CRF in these disorders. Chlordiazepoxide attenuates the“anxiogenic” effects of CRF in both the conflict test [K. T. Britton etal., Psychopharmacology 86:170 (1985); K. T. Britton et al.,Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N.R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. Thebenzodiazepine receptor antagonist (Ro 15-1788), which was withoutbehavioral activity alone in the operant conflict test, reversed theeffects of CRF in a dose-dependent manner while the benzodiazepineinverse agonist (FG 7142) enhanced the actions of CRF [K. T. Britton etal., Psychopharmacology 94:306 (1988)].

It has been further postulated that CRF has a role in immunological,cardiovascular or heart-related diseases such as hypertension,tachycardia and congestive heart failure, stroke and osteoporosis. CRFhas also been implicated in premature birth, psychosocial dwarfism,stress-induced fever, ulcer, diarrhea, post-operative ileus and colonichypersensitivity associated with psychopathological disturbance andstress.

The mechanisms and sites of action through which the standardanxiolytics and antidepressants produce their therapeutic effects remainto be elucidated. It has been hypothesized however, that they areinvolved in the suppression of the CRF hypersecretion that is observedin these disorders. Of particular interest is that preliminary studiesexamining the effects of a CRF receptor antagonist (α-helical CRF₉₋₄₁)in a variety of behavioral paradigms have demonstrated that the CRFantagonist produces “anxiolytic-like” effects qualitatively similar tothe benzodiazepines [for review see G. F. Koob and K. T. Britton, In:Corticotropin-Releasing Factor: Basic and Clinical Studies of aNeuropeptide, E. B. De Souza and C. B Nemeroff eds., CRC Press p221(1990)].

SUMMARY OF THE INVENTION

In one aspect, the present invention provides novel compounds which bindto corticotropin releasing factor receptors, thereby altering theanxiogenic effects of CRF secretion. The compounds of the presentinvention are useful for the treatment of psychiatric disorders andneurological diseases, anxiety-related disorders, post-traumatic stressdisorder, supranuclear palsy and feeding disorders as well as treatmentof immunological, cardiovascular or heart-related diseases and colonichypersensitivity associated with psychopathological disturbance andstress in mammals. According to another aspect, the present inventionprovides novel compounds of Formula I (described below) which are usefulas antagonists of the corticotropin releasing factor. The compounds ofthe present invention exhibit activity as corticotropin releasing factorantagonists and appear to suppress CRF hypersecretion. The presentinvention also includes pharmaceutical compositions containing suchcompounds of Formula I, and methods of using such compounds for thesuppression of CRF hypersecretion, and/or for the treatment ofanxiogenic disorders.

In another aspect, the present invention provides novel compounds,pharmaceutical compositions and methods which may be used in thetreatment of affective disorder, anxiety, depression, irritable bowelsyndrome, post-traumatic stress disorder, supranuclear palsy, immunesuppression, Alzheimer's disease, gastrointestinal disease, anorexianervosa or other feeding disorder, drug or alcohol withdrawal symptoms,drug addiction, inflammatory disorder, fertility problems, disorders,the treatment of which can be effected or facilitated by antagonizingCRF, including but not limited to disorders induced or facilitated byCRF, or a disorder selected from inflammatory disorders such asrheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis andallergies; generalized anxiety disorder; panic, phobias,obsessive-compulsive disorder; post-traumatic stress disorder; sleepdisorders induced by stress; pain perception such as fibromyalgia; mooddisorders such as depression, including major depression, single episodedepression, recurrent depression, child abuse induced depression, andpostpartum depression; dysthemia; bipolar disorders; cyclothymia;fatigue syndrome; stress-induced headache; cancer, humanimmunodeficiency virus (HIV) infections; neurodegenerative diseases suchas Alzbeimer's disease, Parkinson's disease and Huntington's disease;gastrointestinal diseases such as ulcers, irritable bowel syndrome,Crohn's disease, spastic colon, diarrhea, and post operative ilius andcolonic hypersensitivity associated by psychopathological disturbancesor stress; eating disorders such as anorexia and bulimia nervosa;hemorrhagic stress; stress-induced psychotic episodes; euthyroid sicksyndrome; syndrome of inappropriate antidiarrhetic hormone (ADR);obesity; infertility; head traumas; spinal cord trauma; ischemicneuronal damage (e.g., cerebral ischemia such as cerebral hippocampalischemia); excitotoxic neuronal damage; epilepsy; cardiovascular andheart related disorders including hypertension, tachycardia andcongestive heart failure; stroke; immune dysfunctions including stressinduced immune dysfunctions (e.g., stress induced fevers in humans andthe following animal diseases: porcine stress syndrome, bovine shippingfever, equine paroxysmal fibrillation, and dysfunctions induced byconfinement in chickens, sheering stress in sheep or human-animalinteraction related stress in dogs); muscular spasms; urinaryincontinence; senile dementia of the Alzheimer's type; multiinfarctdementia; amyotrophic lateral sclerosis; chemical dependencies andaddictions (e.g., dependencies on alcohol, cocaine, heroin,benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms;osteoporosis; psychosocial dwarfism and hypoglycemia in mammals.

In a further aspect of the invention, the compounds provided by thisinvention (and especially radiolabeled compounds of this invention) arealso useful as standards and reagents in determining the ability of apotential pharmaceutical to bind to the CRF₁ receptor.

The novel compounds encompassed by the instant invention can bedescribed by general Formula I:

wherein

Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen,trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino,carboxamido, lower alkylcarboxamido, N,N-lower dialkylcarboxamido, loweralkyl, lower alkoxy, with the proviso that at least one of the positionsortho or para to the point of attachment of Ar to the tricyclic ringsystem is substituted;

R¹ is hydrogen, halogen, trifluoromethyl, lower alkyl, or (C₁-C₆alkyl)-G¹-R² where G¹ is oxygen or sulfur and R² is hydrogen or C₁-C₆alkyl;

W is N or C—R³ where R³ is hydrogen or lower alkyl;

Q¹ is hydrogen, lower alkyl, halogen, lower alkoxy, amino, methylamino,dimethylamino, hydroxymethyl, or SO_(n)(C₁-C₄ alkyl) where n is 0, 1 or2, cyano, hydroxy, —C(O) (C₁-C₄ alkyl), —CHO, —CO₂(C₁-C₄ alkyl),—CO₂(C₁-C₄ alkenyl), or —CO₂(C₁-C₄ alkynyl);

Q² is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, orlower alkoxy;

X is

wherein

V¹ and V² are CH₂, CO, CS, SO₂ or CH(lower alkyl), with the proviso thatboth V¹ and V² cannot both be CO, CS or SO₂;

Y¹ and Y² independently represent a bond or lower alkylene;

A¹ is NR⁴R⁵ wherein R⁴ and R⁵ are independently hydrogen or a loweralkyl group which optionally forms a heterocycloalkyl group with Y¹;

lower alkanoyl, lower alkylsulfonyl, with the proviso that R⁴ and R⁵cannot both be alkanoyl or alkylsulfonyl; or

NR⁴R⁵ taken together form a C₃-C₆ heterocycloalkyl or a group of theformula:

 wherein e and f are independently 1, 2 or 3 and the sum of e and f isat least 3; and

G² is

NR⁶ wherein R⁶ is hydrogen or lower alkyl, or

CH(C₀-C₆ alkylene)—G³—R⁷ wherein G³ is CONH, CONH(lower alkyl), NH,NH(lower alkyl) and R⁷ is hydrogen or lower alkyl; or

CONH₂, CO[N(lower alkyl)R⁸] wherein R⁸ is hydrogen or lower alkyl;

A² is hydrogen, lower alkyl, (C₁-C₆ alkylene)—G⁴—R⁹ wherein G⁴ is oxygenor sulfur and R⁹ is hydrogen, trifluoromethyl or lower alkyl;

wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-,2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-,3- or 4pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono- or disubstituted withhalogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with theproviso that tetrazolyl can have at most one substituent;

Z¹ is lower alkyl; and

V², Y² and A² are as defined above;

where

Z² is carbon or nitrogen;

 where

when Z² is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3,

R¹⁰ is carboxamido, or (lower alkylene)-G⁵—R¹¹

wherein G⁵ is NH, NH(lower alkyl) and R¹¹ is hydrogen or lower alkyl;

when Z² is carbon, n is 1 or 2 and p is 1 or 2, R¹⁰ is amino; or

when Z² is nitrogen, n is 1 or 2 and p is 1 or 2, R¹⁰ is hydrogen; or

(iv) a nitrogen heterocycle of the formula:

wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, orpyrazolyl, each of which is optionally substituted with amino,trifluoromethyl, carboxamido, or (lower alkylene)-G⁶—R¹² wherein G⁶ isNH, NH(lower alkyl) and R¹² is hydrogen or lower alkyl.

The compounds of Formula I are antagonists at the. CRF₁ receptor and areuseful in the diagnosis and treatment of stress related disorders suchas post traumatic stress disorder (PTSD) as well as depression, headacheand anxiety.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by general Formula I:

wherein

Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen,trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino,carboxamido, lower alkylcarboxamido, N,N-lower dialkylcarboxamido, loweralkyl, lower alkoxy, with the proviso that at least one of the positionsortho or para to the point of attachment of Ar to the tricyclic ringsystem is substituted;

R¹ is hydrogen, halogen, trifluoromethyl, lower alkyl, or (C₁-C₆alkyl)-G¹—R² where G¹ is oxygen or sulfur and R² is hydrogen or C₁-C₆alkyl;

W is N or C—R³ where R³ is hydrogen or lower alkyl;

Q¹ is hydrogen, lower alkyl, halogen, lower alkoxy, amino, methylamino,dimethylamino, hydroxymethyl, or SO_(n)(C₁-C₄ alkyl) where n is 0, 1 or2, cyano, hydroxy, —C(O) (C₁-C₄ alkyl), —CHO, —CO₂(C₁-C₄ alkyl),—CO₂(C₁-C₄ alkenyl), or —CO₂(C₁-C₄ alkynyl);

Q² is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, orlower alkoxy;

X is

wherein

V¹ and V² are CH₂, CO, CS, SO₂ or CH(lower alkyl), with the proviso thatboth V¹ and V² cannot both be CO, CS or SO₂;

Y¹ and Y² independently represent a bond or lower alkylene;

A¹ is NR⁴R⁵ wherein R⁴ and R⁵ are independently hydrogen or a loweralkyl group which optionally forms a heterocycloalkyl group with Y¹;

lower alkanoyl, lower alkylsulfonyl, with the proviso that R⁴ and R⁵cannot both be alkanoyl or alkylsulfonyl; or

NR⁴R⁵ taken together form a C₃-C₆ heterocycloalkyl or a group of theformula:

wherein e and f are independently 1, 2 or 3 and the sum of e and f is atleast 3; and

G² is

NR⁶ wherein R⁶ is hydrogen or lower alkyl, or

CH(C₀-C₆ alkylene)-G³—R⁷ wherein G³ is CONH, CONH(lower alkyl), NH,NH(lower alkyl) and R⁷ is hydrogen or lower alkyl; or

CONH₂, CO[N(lower alkyl)R⁸] wherein R⁸ is hydrogen or lower alkyl;

A² is hydrogen, lower alkyl, (C₁-C₆ alkylene)-G⁴—R⁹ wherein G⁴ is oxygenor sulfur and R⁹ is hydrogen, trifluoromethyl or lower alkyl;

wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-,2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-,3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono- or disubstituted withhalogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with theproviso that tetrazolyl can have at most one substituent;

Z¹ is lower alkyl; and

V², Y² and A² are as defined above;

where

Z² is carbon or nitrogen;

 where

when Z² is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3,

R¹⁰ is carboxamido, or (lower alkylene)-G⁵—R¹¹

wherein G⁵ is NH, NH(lower alkyl) and R¹¹ is hydrogen or lower alkyl;

when Z² is carbon, n is 1 or 2 and p is 1 or 2, R¹⁰ is amino; or

when Z² is nitrogen, n is 1 or 2 and p is 1 or 2, R¹⁰ is hydrogen; or

(iv) a nitrogen heterocycle of the formula:

wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, orpyrazolyl, each of which is optionally substituted with amino,trifluoromethyl, carboxamido, or (lower alkylene)-G⁶—R¹² wherein G⁶ isNH, NH(lower alkyl) and R¹² is hydrogen or lower alkyl.

Preferred compounds of the invention have formula II:

wherein

each R_(a) independently represents lower alkyl;

Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen,trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino,carboxamido, lower alkylcarboxamido, N,N-lower dialkylcarboxamido, loweralkyl, lower alkoxy, with the proviso that at least one of the positionsortho or para to the point of attachment of Ar to the tricyclic ringsystem is substituted;

R¹ is hydrogen, halogen, trifluoromethyl, lower alkyl, or (C₁-C₆alkyl)-G¹—R² where G¹ is oxygen or sulfur and R² is hydrogen or C₁-C₆alkyl;

W is N or C—R³ where R³ is hydrogen or lower alkyl;

Q¹ is hydrogen, lower alkyl, halogen, lower alkoxy, amino, methylamino,dimethylamino, hydroxymethyl, or SO_(n)(C₁-C₄ alkyl) where n is 0, 1 or2, cyano, hydroxy, —C(O) (C₁-C₄ alkyl), —CHO, —CO₂(C₁-C₄ alkyl),—CO₂(C₁-C₄ alkenyl), or —CO₂(C₁-C₄ alkynyl);

Q² is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, orlower alkoxy;

X is

wherein

V¹ and V² are CH₂, CO, CS, SO₂ or CH(lower alkyl), with the proviso thatboth V¹ and V² cannot both be CO, CS or SO₂;

Y¹ and Y² independently represent a bond or lower alkylene;

A¹ is NR⁴R⁵ wherein R⁴ and R⁵ are independently hydrogen or a loweralkyl group which optionally forms a heterocycloalkyl group with Y¹;

lower alkanoyl, lower alkylsulfonyl, with the proviso that R⁴ and R⁵cannot both be alkanoyl or alkylsulfonyl; or

NR⁴R⁵ taken together form a C₃-C₆ heterocycloalkyl or a group of theformula:

wherein e and f are independently 1, 2 or 3 and the sum of e and f is atleast 3; and

G² is

NR⁶ wherein R⁶ is hydrogen or lower alkyl, or

CH(C₀-C₆ alkylene)-G³—R⁷ wherein G³ is CONH,

CONH(lower alkyl), NH, NH(lower alkyl) and R⁷ is hydrogen or loweralkyl; or

CONH₂, CO[N(lower alkyl)R⁸] wherein R⁸ is hydrogen or lower alkyl;

A² is hydrogen, lower alkyl, (C₁-C₆ alkylene)-G⁴—R⁹ wherein G⁴ is oxygenor sulfur and R⁹ is hydrogen, trifluoromethyl or lower alkyl;

wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-,2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-,3- or 4-pyrazolyl, 1-, 3- or 4-triazolyi, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono- or disubstituted withhalogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with theproviso that tetrazolyl can have at most one substituent;

Z¹ is lower alkyl; and

V², Y² and A² are as defined above;

where

Z² is carbon or nitrogen;

 where

when Z² is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3,

R¹⁰ is carboxamido, or (lower alkylene)-G⁵—R¹¹ wherein G⁵ is NH,NH(lower alkyl) and R¹¹ is hydrogen or lower alkyl;

when Z² is carbon, n is 1 or 2 and p is 1 or 2, R¹⁰ is amino; or

when Z² is nitrogen, n is 1 or 2 and p is 1 or 2, R¹⁰ is hydrogen; or

(iv) a nitrogen heterocycle of the formula:

wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, orpyrazolyl, each of which is optionally substituted with amino,trifluoromethyl, carboxamido, or (lower alkylene)-G⁶—R¹² wherein G⁶ isNH, NH(lower alkyl) and R¹² is hydrogen or lower alkyl.

In Formula II, Q¹ and Q² preferably independently represent hydrogen,methyl, or ethyl. More preferred compounds of Formula II are those whereN—V²—Y²—A² represents N-cyclopropylmethyl. Other more preferredcompounds of Formula II include those where one of Q¹ and Q² is methylor ethyl and the other is hydrogen.

Still other more preferred compounds of Formula II are those whereN—V²—Y²—A² represents N-cyclopropylmethyl, Q¹ is methyl or ethyl, and—V¹—Y¹—A¹ represents

hereinafter Formula II-a,

wherein

R_(b) is hydrogen or methyl;

t is 1, 2 or 3, more preferably 1;

R_(x) is hydrogen, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl where phenyl isoptionally mono- or disubstituted independently with C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, or hydroxy; and

R_(y) is hydrogen, C₁-C₆ alkyl, (C₃-C₆)cycloalkyl; or

NR_(x)R_(y) represents pyrrolidinyl, N-(C₁-C₆)alkylpyrrolidin-2-yl,piperidinyl, morpholinyl, or N-(C₁-C₆)alkylpiperazinyl.

Particularly preferred compounds of Formula II include those whereN—V²—Y²—A² represents N-cyclopropylmethyl, Q¹ is methyl, and —V¹—Y¹—A¹represents II-a where R_(b) is hydrogen, and t is 1. Particularlypreferred R_(x) and R_(y) groups are independently hydrogen or C₁-C₂alkyl, or where NR_(x)R_(y) represents pyrrolidinyl, piperidinyl orpiperazinyl.

Other preferred compounds of the invention have formula III:

wherein

each R_(a) independently represents lower alkyl;

Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen,trifluoromethyl, hydroxy, amino, lower alkylamino, lower dialkylamino,carboxamido, lower alkylcarboxamido, N,N-lower dialkylcarboxamido, loweralkyl, lower alkoxy, with the proviso that at least one of the positionsortho or para to the point of attachment of Ar to the tricyclic ringsystem is substituted;

R¹ is hydrogen, halogen, trifluoromethyl, lower alkyl, or (C₁-C₆alkyl)-G¹—R² where G¹ is oxygen or sulfur and R² is hydrogen or C₁-C₆alkyl;

W is N or C—R³ where R³ is hydrogen or lower alkyl;

Q¹ is hydrogen, lower alkyl, halogen, lower alkoxy, amino, methylamino,dimethylamino, hydroxymethyl, or SO_(n)(C₁-C₄ alkyl) where n is 0, 1 or2, cyano, hydroxy, —C(O)(C₁-C₄ alkyl), —CHO, —CO₂(C₁-C₄ alkyl),—CO₂(C₁-C₄ alkenyl), or —CO₂ (C₁-C₄ alkynyl);

Q² is hydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, orlower alkoxy;

X is

wherein

V¹ and V² are CH₂, CO, CS, SO₂ or CH(lower alkyl), with the proviso thatboth V¹ and V² cannot both be CO, CS or SO₂;

Y¹ and Y² independently represent a bond or lower alkylene;

A¹ is NR⁴R⁵ wherein R⁴ and R⁵ are independently hydrogen or a loweralkyl group which optionally forms a heterocycloalkyl group with Y¹;

lower alkanoyl, lower alkylsulfonyl, with the proviso that R⁴ and R⁵cannot both be alkanoyl or alkylsulfonyl; or

NR⁴R⁵ taken together form a C₃-C₆ heterocycloalkyl or a group of theformula:

wherein e and f are independently 1, 2 or 3 and the sum of e and f is atleast 3; and

G² is

NR⁶ wherein R⁶ is hydrogen or lower alkyl, or CH(C₀-C₆ alkylene)-G³—R⁷wherein G³ is CONH, CONH(lower alkyl), NH, NH(lower alkyl) and R⁷ ishydrogen or lower alkyl; or

CONH₂, CO[N(lower alkyl)R⁸] wherein R⁸ is hydrogen or lower alkyl;

A² is hydrogen, lower alkyl, (C₁-C₆ alkylene)-G⁴—R⁹

wherein G⁴ is oxygen or sulfur and R⁹ is hydrogen, trifluoromethyl orlower alkyl;

wherein heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-,2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 1-,3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or5-tetrazolyl, each of which is optionally mono- or disubstituted withhalogen, trifluoromethyl, amino, lower alkyl, lower alkoxy, with theproviso that tetrazolyl can have at most one substituent;

Z¹ is lower alkyl; and

V², Y² and A² are as defined above;

where

Z² is carbon or nitrogen;

 where

is when Z² is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3,

R¹⁰ is carboxamido, or (lower alkylene)-G⁵—R¹¹

wherein G⁵ is NH, NH(lower alkyl) and R¹¹ is hydrogen or lower alkyl;

when Z² is carbon, n is 1 or 2 and p is 1 or 2, R¹⁰ is amino; or

when Z² is nitrogen, n is 1 or 2 and p is 1 or 2, R¹⁰ is hydrogen; or

(iv) a nitrogen heterocycle of the formula:

wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, orpyrazolyl, each of which is optionally substituted with amino,trifluoromethyl, carboxamido, or (lower alkylene)-G⁶—R¹² wherein G⁶ isNH, NH(lower alkyl) and R¹² is hydrogen or lower alkyl.

In Formula III, Q¹ and Q² preferably independently represent hydrogen,methyl, or ethyl. Particularly preferred compounds of Formula III arethose where N—V²—Y²—A² represents N-cyclopropylmethyl. Other morepreferred compounds of Formula III include those where one of Q¹ and Q²is methyl or ethyl and the other is hydrogen.

Still other more preferred compounds of Formula III are those whereN—V²—Y²—A² represents N-cyclopropylmethyl, Q¹ is methyl or ethyl, and—V¹—Y¹—A¹ represents

hereinafter Formula III-a,

wherein

R_(b) is hydrogen or methyl;

t is 1, 2 or 3, more preferably 1;

R_(x) is hydrogen, C₁-C₆ alkyl, phenyl(C₁-C₆)alkyl where phenyl isoptionally mono- or disubstituted independently with C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, or hydroxy; and

R_(y) is hydrogen, C₁-C₆ alkyl, (C₃-C₆)cycloalkyl; or NR_(x)R_(y)represents pyrrolidinyl, N-(C₁-C₆)alkylpyrrolidin-2-yl, piperidinyl,morpholinyl, or N-(C₁-C₆)alkylpiperazinyl.

Particularly preferred compounds of Formula III include those whereN—V²—Y²—A² represents N-cyclopropylmethyl, Q¹ is methyl, and —V¹—Y¹—A¹represents III-a where R_(b) is hydrogen, and t is 1. Particularlypreferred R_(x) and R_(y) groups are independently hydrogen or C₁-C₂alkyl, or where NR_(x)R_(y) represents pyrrolidinyl, piperidinyl orpiperazinyl.

Preferred compounds of the invention include the following:

4-(N-(2-Pyrrolidinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine

4-(N-(2-Pyrrolidinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine

4-(N-(2-Piperidinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine

4-(N-(2-Morpholinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine

4-(N-(2-Piperazinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine

4-(N-(2-Morpholinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyrimidine

4-(N-(2-Piperazinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyrimidine

4-(N-(2-Methylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine

4-(N-(2-Dimethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine

4-(N-(2-Ethylmethylamino)ethyl-N-cyclopropylmethyl)-amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine

4-(N-(2-Ethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine

4-(N-(2-Diethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine

4-(N-(2-Piperazinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine

4-(N-(2-(4-Methylpiperazinyl))ethyl-N-cyclopropyl-methyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine

In certain situations, the compounds of Formula I may contain one ormore asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable acid addition salts. In addition,if the compound of the invention is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)n—ACOOH where nis 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By “alkyl”, “lower alkyl”, or C₁-C₆ alkyl in the present invention ismeant straight or branched chain alkyl groups having 1-6 carbon atomsoptionally forming a 3 to 6 atoms carbocycle, such as, for example,methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl,n-butyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, 2-pentyl, isopentyl,neopentyl, cyclopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl,cyclohexyl.

By C₀-C₆ alkylene is meant a direct bond or a C₁-C₆ alkylene group,optionally forming a 3 to 6 atoms carbocycle, such as methylene,ethylidene, propylidene, butylidene, pentylidene, cyclopentylidene,hexylidene, cyclohexylidene.

By “alkoxy”, “lower alkoxy”, or C₁-C₆ alkoxy in the present invention ismeant straight or branched chain alkoxy groups having 1-6 carbon atomsoptionally forming a 3 to 6 atoms carbocycle, such as, for example,methoxy, ethoxy, propoxy, isopropoxy, cyclopropylmethoxy, n-butoxy,sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy,cyclopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, cyclohexoxy.

By “alkanoyl”, “lower alkanoyl”, or C₁-C₆ alkanoyl in the presentinvention is meant straight or branched chain alkanoyl groups having 1-6carbon atoms optionally forming a 3 to 6 atoms carbocycle, such as, forexample, acetyl, propionyl, isopropionyl, cyclopropionyl, butanoyl,pentanoyl, cyclopentanoyl, hexanoyl, cyclhexanoyl.

CONH represents an amide functional group, i.e.,

The term “heterocycle” or “heterocycloalkyl” means a monocyclic orbicyclic hydrocarbon group which in which one or more of the ring carbonatoms has been replaced with a heteroatom, e.g., oxygen, sulfur ornitrogen. Such groups preferably have 4 to 10 carbon atoms and 1 to 4heteroatoms.

By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine.

The interaction of aminoalkyl substituted pyrrolo[3,2-e]pyridine andpyrrolo[2,3-b]pyrimidine derivatives of the invention with CRF₁receptors is shown in the examples below. This interaction results inthe pharmacological activities of these compounds as illustrated inrelevant animal models.

As the compounds of Formula I are effective CRF₁ receptor antagonists,they are useful for the treatment of psychiatric disorders, neurologicaldiseases, immunological, cardiovascular or heart-related diseases andcolonic hypersensitivity associated with psychopathological disturbanceand stress.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachid oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachid oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active 5 ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preparation of Aminoalkyl Substituted Pyrrolo[3,2-e]pyridine andPyrrolo[2,3-b]pyrimidine Analogues

An illustration of the preparation of compounds of the present inventionis given in Scheme I, Scheme II and Scheme III. Those having skill inthe art will recognize that the starting materials may be varied andadditional steps employed to produce compounds encompassed by thepresent invention.

wherein Ar, Q¹, Q², R¹ and R³ are as defined above for Formula I; andR¹⁴, R¹⁵ and R¹⁶ are encompassed by the definition of X for Formula I.

wherein Ar, Q¹, Q², R¹ and R³ are as defined above for Formula I; andR¹⁵ and R¹⁶ are encompassed by the definition of X for Formula I.

wherein Ar, Q¹, Q² and R¹ are as defined above for Formula I; and R¹⁵,R¹⁶ and R¹⁷ are encompassed by the definition of X for Formula I.

The disclosures of all articles and references mentioned in thisapplication, including patents, are incorporated herein by reference.

The preparation of the compounds of the present invention is illustratedfurther by the following Examples, which are not to be construed aslimiting the invention in scope or spirit to the specific procedures andcompounds described in them.

Commercial reagents are used without further purification. THF refers totetrahydrofuran. Room or ambient temperature refers to 20 to 25° C.Concentration implies the use of a rotary evaporator. TLC refers to thinlayer chromatography. Mass spectral data are obtained either by CI orAPCI methods.

EXAMPLE 1

A.4-(N-Cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine

A solution of dichloroethane (70 mL) containing4-amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine (11g) and cyclopropanecarbonyl chloride (3.4 mL) at reflux is treated withdropwise addition of N,N-diisopropylethylamine (6.6 mL). After heatingfor 0.5 hour the reaction is cooled to ambient temperature and pouredinto aqueous potassium carbonate solution. The product is extracted withdichloromethane, dried over sodium sulfate, filtered and concentrated.The concentrate is re-dissolved in THF (100 mL) and mixed withborane-methyl sulfide complex (10M, 10.3 mL). The mixture is heated toreflux for 8 hours and quenched at room temperature with a large excessof methanol (about 100 mL). Re-heat mixture to reflux for 1 hour, thenconcentrate under reduced pressure. More methanol (another 50 mL) isadded to the gummy residue and the solution is re-concentrated to yielda white solid.

B.4-(N-(2-Chloroethyl)-N-cyclopropylmethyl)amino-3,6dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine

A solution containing the product from Example 1A (13 g) andchloroacetyl chloride (3 mL) in dichloroethane (100 mL) is refluxed for4 hours. The solvent and excess reagent are removed under reducedpressure. Aqueous potassium carbonate is added to the remaining oilyresidue and extracted with dichloromethane. The extract is dried withsodium sulfate, filtered and concentrated. The latter chloroacetylcompound (15 g) is dissolved in THF (100 mL). Add borane-methyl sulfidecomplex (10M, 3.4 mL) and stir at ambient temperature for 15 minutesthen for 1 hour at reflux temperature. The solution is cooled back toroom temperature, quenched with a large excess of methanol (50 mL) andre-heated to reflux for 1 hour. The solution is then concentrated.

C.4-(N-(2-Dimethylamino)ethyl-N-cyclopropylmethyl)-amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo2,3-b]pyridine(Compound 1)

A steel bomb containing the product from Example 1B (3.8 g),dimethylamine (8 mL) and N-methylpyrrolidinone (20 mL) is sealed andheated to 80° C. for 10 hours. The mixture is poured into water andextracted with ethyl acetate. The organic layer is washed with water,dried over sodium sulfate, filtered and concentrated.

EXAMPLE 2

The following compounds are prepared essentially according to theprocedures set forth in Example 1 and/or Schemes I, II, and III.

a)4-(N-(2-Methylamino)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(Compound 2)

b)4-(N-(2-Pyrrolidinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(Compound 3)

c)4-(N-(2-Ethylmethylamino)ethyl-N-cyclopropylmethyl)-amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(Compound 4)

d)4-(N-(2-Ethylamino)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(Compound 5)

e)4-(N-(2-Diethylamino)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(Compound6)

f)4-(N-(2-Piperidinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(Compound 7)

g)4-(N-(2-Morpholinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(Compound 8)

h)4-(N-(2-Piperazinyl)ethyl-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(Compound 9)

i)4-(N-(2-(4-Methylpiperazinyl))ethyl-N-cyclopropyl-methyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(Compound 10)

EXAMPLE 3

4-(N-(2-Aminoethyl)-N-cyclopropylmethyl)amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(Compound 11)

A solution containing the product from Example 1B (500 mg) and sodiumazide (22 mg) in N-methylpyrrolidinone (5 mL) is heated to 120° C. for 2hours. The mixture is poured into water and extracted with ethylacetate. The organic layer is washed with water, dried over sodiumsulfate, filtered and concentrated. An ethanol (10 mL) solution of thecrude product and 10% palladium on carbon (about 200 mg) is hydrogenatedfor 8 hours at approximately 1 atmosphere pressure. The suspension isfiltered over celite and concentrated.

EXAMPLE 4

A. 4-Chloro-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine

Dissolve tert-butylnitrite (0.65 g) in acetonitrile (10 mL) and addcopper(II)chloride (0.68 g). Then4-amino-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(1.33 g) is added portionwise to the greenish-brown solution and themixture is stirred for 12 hours. The acetonitrile is removed byevaporation and the residue is partitioned between water anddichloromethane. The aqueous layer is extracted with moredichloromethane and the combined extract is washed with water, driedover sodium sulfate, filtered and concentrated.

B.4-Piperazinyl-3,6-dimethyl-1-(2,4,6-trimethylphenyl)pyrrolo[2,3-b]pyridine(Compound 12)

Combine the compound from Example 4A (200 mg) and piperazine (0.58 g) inN-methylpyrrolidinone (2 mL) and heat the solution to 120° C. for 12hours. Pour mixture into water and extract with ethyl acetate. Washextract with aqueous ammonium chloride then water. Dry extract oversodium sulfate, filter and concentrate.

EXAMPLE 5

A.4-(N-Cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine

A mixture containing4-chloro-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine(450 mg), cyclopropylmethylamine hydrochloride (800 mg) andtriethylamine (1.3 mL) in N-methylpyrrolidinone (3 mL) is heated to 110°C. in a sealed tube for 4 hours. Dilute mixture with ethyl acetate andwash with water, aqueous ammonium chloride and brine. Dry over sodiumsulfate, filter and concentrate to give a tan colored solid: MS 335(M+H).

B.4-(N-(2-Pyrrolidinyl)ethyl-N-cyclopropylmethyl)-amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2e]pyrimidine(Compound 13)

To a solution of the compound from Example 5A (130 mg) inN,N-dimethylformamide (1 mL) at 0° C., under a blanket of nitrogen, isadded sodium hydride (60%, 70 mg). After stirring the solution for 0.5hours, 2-dimethylaminoethyl chloride hydrochloride (135 mg) is added.The mixture is then heated to 40° C. for 2 hours, then quenched with iceand water. Dilute with ethyl acetate and wash with water, brine, dryover sodium sulfate, filter and concentrate. Purify by preparative TLCusing 10% methanol and 0.5% ammonium hydroxide in dichloromethane aseluent to obtain 100 mg of product: MS 432 (M+H).

EXAMPLE 6

The following compounds are prepared essentially according to theprocedures set forth in Example 5 and/or Schemes I, II, and III.

a)4-(N-(2-Methylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine(Compound 14)

b)4-(N-(2-Dimethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine(Compound 15)

c)4-(N-(2-Ethylmethylamino)ethyl-N-cyclopropylmethyl)-amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine(Compound 16)

d)4-(N-(2-Ethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine(Compound 17)

e)4-(N-(2-Diethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine(Compound 18)

f)4-(N-(2-Piperidinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine(Compound 19)

g)4-(N-(2-Morpholinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine(Compound 20)

h)4-(N-(2-Piperazinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine(Compound 21)

i)4-(N-(2-(4-Methylpiperazinyl))ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine(Compound 22)

EXAMPLE 7

The pharmaceutical utility of compounds of this invention are indicatedby the following assays for human CRF₁ receptor activity.

Assay for Recombinant Human CRF₁ Receptor Binding Activity

CRF receptor binding is performed using a modified version of the assaydescribed by Grigoriadis and De Souza (Methods in Neurosciences, Vol. 5,1991). Membrane pellets containing CRF receptors are re-suspended in 50mM Tris buffer pH 7.7 containing 10 mM MgCl₂ and 2 mM EDTA andcentrifuged for 10 minutes at 48000 g. Membranes are washed again andbrought to a final concentration of 1500 mg/ml in binding buffer (Trisbuffer above with 0.1% BSA, 15 mM bacitracin and 0.01 mg/mL aprotinin.).For the binding assay, 100 mL of the membrane preparation is added to 96well microtube plates containing 100 mL of ¹²⁵I-CRF (SA 2200 Ci/mmol,final concentration of 100 pM) and 50 mL of drug. Binding is carried outat room temperature for 2 hours. Plates are then harvested on a Brandel96 well cell harvester and filters are counted for gamma emissions on aWallac 1205 Betaplate liquid scintillation counter. Non specific bindingis defined by 1 mM cold CRF. IC₅₀ values are calculated with thenon-linear curve fitting program RS/1 (BBN Software Products Corp.,Cambridge, Mass). The binding affinity for the compounds of Formula Iexpressed as IC₅₀ value, generally ranges from about 0.5 nanomolar toabout 10 micromolar.

Alternatively, the binding activity of the compounds of formula I to thehuman CRF₁ receptor can be measured as follows:

Assay for Human CRF Receptor Binding Activity in IMR32 Cells

[¹²⁵I]Sauvagine Binding to CRF₁ Receptors Endogenously Expressed inIMR-32 Cells: IMR-32 human neuroblastoma cells are grown to 80%confluence in EMEM containing Earle's Balanced Salts and 2 mM1-glutamine with 10% FBS, 25 mM HEPES, 1 mM Sodium Pyruvate, andnonessential amino acids. At this time, flasks of cells are treated with2.5 μM 5-bromo-2′-deoxyuridine (Br-dU) for 10 days. Media is changedevery 3-4 days across the 10 day period. Cells are harvested usingNo-Zyme (JRH Biosciences) and rinsed with PBS. For membrane preparation,cells are homogenized in wash buffer (50 mM Tris HCl, 10 mM MgCl₂, 2 mMEGTA, pH 7.4) and centrifuged at 48,000×g for 10 minutes at 4° C.Pellets are re-suspended, homogenized and centrifuged two additionaltimes. The receptor binding assay is performed using assay buffer (50 mMTris HCl, 10 mM MgCl₂, 2 mM EGTA, pH 7.4, 0.1% BSA, 0.1 mM bacitracin(22.0 mg/100 mL)), 150 μg protein/tube, and [¹²⁵I]Sauvagine (NEN; 100 pMfor competition analysis and 10 pM-1 nM for saturation analysis) toyield a final volume of 200 uL. Nonspecific binding is defined using 2μM r/h CRF or 9-41 alpha-helical CRF. Cells are incubated for 2 hours atroom temperature. The assay is terminated by rapid vacuum filtration(Tomtec: Deepwell 3) through GFC filters presoaked in 1% PEI usingice-cold 50 mM Tris HCl and dry thoroughly by air. Specific Binding:70-80%; Kd (nM): 0.30 nM; Bmax (fmole/mg protein): 40-50. IC₅₀ valuesare calculated with the non-linear curve fitting program RS/1 (BBNSoftware Products Corp., Cambridge, Mass.).

The binding affinity for the compounds of Formula I expressed as IC₅₀value, generally ranges from about 0.5 nanomolar to about 10 micromolar.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula:

or a pharmaceutically acceptable salt thereof wherein Ar is phenyl, 1-or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionallymono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy,amino, lower alkylamino, lower dialkylamino, carboxamido, loweralkylcarboxamido, N,N-lower dialkylcarboxamido, lower alkyl, loweralkoxy, with the proviso that at least one of the positions ortho orpara to the point of attachment of Ar to the bicyclic ring system issubstituted; R¹ is hydrogen, halogen, trifluoromethyl, lower alkyl, or(C₁-C₆ alkyl)-G¹—R² where G¹ is oxygen or sulfur and R² is hydrogen orC_(1-C) ₆ alkyl; Q¹ is hydrogen, lower alkyl, halogen, lower alkoxy,amino, methylamino, dimethylamino, hydroxymethyl, or SO_(n)(C₁-C₄ alkyl)where n is 0, 1 or 2, cyano, hydroxy, —C(O) (C₁-C₄ alkyl), —CHO,—CO₂(C₁-C₄ alkyl), —CO₂(C₁-C₄ alkenyl), or —CO₂ (C₁-C₄ alkynyl); Q² ishydrogen, lower alkyl, halogen, hydroxymethyl, methoxymethyl, or loweralkoxy; and X is a group of the formula

 wherein V¹ is CH₂ or CH(lower alkyl); Y¹ represents a bond or loweralkylene; A¹ is NR⁴R⁵ wherein R⁴ and R⁵ are independently lower alkyl;or A¹ is NR⁴R⁵ wherein R⁴ and R⁵ are taken together to form amorpholinyl, piperazinyl, piperidinyl, or pyrrolidinyl group.
 2. Acompound according to claim 1, wherein Q¹ and Q² are independentlymethyl or ethyl.
 3. A compound according to claim 1, wherein Q¹ ismethyl, Q² is hydrogen or methyl, R¹ is methyl, Ar is2,4,6-trimethylphenyl, and X is(N-(2-pyrrolidinyl)ethyl-N-cyclopropylmethyl)amino or(N-(2-dimethylamino)ethyl-N-cyclopropylmethyl)amino.
 4. A compound ofthe formula

or a pharmaceutically acceptable salt thereof, wherein each R_(a) isindependently lower alkyl; R_(b) is hydrogen or methyl; t is 1, 2, or 3;R_(x) is hydrogen, C₁-C₆alkyl, phenyl (C₁-C₆)alkyl where phenyl isoptionally mono- or disubstituted independently with C₁-C₆ alkyl,C₁-C₆alkoxy, halogen, or hydroxy; and R_(y) is hydrogen, C₁-C₆ alkyl,(C₃-C₆)cycloalkyl; or NR_(x)R_(y) represents pyrrolidinyl,N-(C₁-C₆)alkylpyrrolidin-2-yl, piperidinyl, morpholinyl, orN-(C₁-C₆)alkylpiperazinyl; Q¹ and Q² independently represent hydrogen,methyl, or ethyl; and R¹ is hydrogen, halogen, trifluoromethyl, loweralkyl, or (C₁-C₆ alkyl)-G¹—R² where G¹ is oxygen or sulfur and R² ishydrogen or C₁-C₆ alkyl.
 5. A compound or salt according to claim 1which is4-(N-(2-Pyrrolidinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.6. A compound or salt according to claim 1 which is4-(N-(2-Methylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.7. A compound or salt according to claim 1 which is4-(N-(2-Dimethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.8. A compound or salt according to claim 1 which is4-(N-(2-Ethylmethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.9. A compound or salt according to claim 1, which is4-(N-(2-Ethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.10. A compound or salt according to claim 1 which is4-(N-(2-Diethylamino)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.11. A compound or salt according to claim 1 which is4-(N-Cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.12. A compound or salt according to claim 1 which is4-(N-(2-Pyrrolidinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.13. A compound or salt according to claim 10 which is4-(N-(2-Piperidinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.14. A compound or salt according to claim 1 which is4-(N-(2-Morpholinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.15. A compound or salt according to claim 1 which is4-(N-(2-Piperazinyl)ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.16. A compound or salt according to claim 1 which is4-(N-(2-(4-Methylpiperazinyl))ethyl-N-cyclopropylmethyl)amino-2,5-dimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[3,2-e]pyrimidine.17. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 1. 18. A method of treatinganxiety, depression, or post-traumatic stress disorder comprisingadministering a therapeutically effective amount of a compound of claim1 to a patient in need thereof.